Lopez-Contreras Andres J, Specks Julia, Barlow Jacqueline H, Ambrogio Chiara, Desler Claus, Vikingsson Svante, Rodrigo-Perez Sara, Green Henrik, Rasmussen Lene Juel, Murga Matilde, Nussenzweig André, Fernandez-Capetillo Oscar
Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain;
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
Genes Dev. 2015 Apr 1;29(7):690-5. doi: 10.1101/gad.256958.114.
In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.
在酿酒酵母中，当存在增加核糖核苷酸还原酶（RNR）复合物活性的突变时，检查点激酶Mec1（ATR）缺失的细胞仍可存活。该途径在哺乳动物中是否保守尚不清楚。在此我们表明，携带RNR调节亚基RRM2额外等位基因（Rrm2(TG)）的小鼠细胞具有超生理水平的RNR活性，并且在脆弱位点处的染色体断裂减少。此外，增加Rrm2基因剂量可显著延长ATR突变小鼠的寿命。我们的研究揭示了哺乳动物中首个通过增加RNR活性来降低脆弱位点表达并减轻早衰样疾病严重程度的遗传条件。
